Aluminum-catalyzed asymmetric alkylations of pyridyl-substituted alkynyl ketones with dialkylzinc reagents

Article abstract of DOI:10.1021/ja802935w

Alkylations of pyridyl-substituted ynones with Et₂Zn and Me ₂Zn, promoted by amino acid-based chiral ligands in the presence of Al-based alkoxides, afford tertiary propargyl alcohols efficiently in 57% to >98% ee. Two easily accessib

Full text of DOI:10.1021/ja802935w

Published on Web 06/28/2008
Aluminum-Catalyzed Asymmetric Alkylations of
Pyridyl-Substituted Alkynyl Ketones with Dialkylzinc Reagents
Donna K. Friel, Marc L. Snapper,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
Received April 21, 2008; E-mail: amir.hoveyda@bc.edu
Abstract: Alkylations of pyridyl-substituted ynones with Et2Zn and Me2Zn, promoted by amino acid-based
chiral ligands in the presence of Al-based alkoxides, afford tertiary propargyl alcohols efficiently in 57% to
>98% ee. Two easily accessible chiral ligands are identified as optimal for reactions of the two dialkylzinc
reagents. Catalytic alkylations with Et2Zn require a chiral ligand carrying two amino acid moieties (valine
and phenylalanine) along with a p-trifluoromethylphenylamide C-terminus. In contrast, reactions with Me2Zn
are most effectively promoted in the presence of a chiral ligand containing a single amino acid (benzyl
cysteine), capped by an n-butylamide. Enantiomerically enriched tertiary alcohols bearing a pyridyl and an
alkyne substituent can be functionalized in a variety of manners to furnish a wide range of difficult-to-
access acyclic and heterocyclic structures; two noteworthy examples are Cu-catalyzed protocols for
conversion of tertiary propargyl alcohols to enantiomerically enriched tetrasubstituted allenes and bicyclic
amides that bear an N-substituted quaternary carbon stereogenic center. Mechanistic models that account
for the trends and enantioselectivity levels are provided.
Scheme 1. Catalytic Asymmetric Alkylations of Pyridyl Ynones and
Introduction
Applications to Enantioselective Synthesis of Difficult-to-Access
Development of chiral catalysts for enantioselective synthesis
of tertiary alcohols is a challenging and important goal of
modern chemical synthesis.1 Nevertheless, in spite of recent
advances,2 catalytic additions of carbon-based nucleophiles to
ketones, perhaps the most direct route to synthesis of enantio-
merically enriched tertiary alcohols, remain underdeveloped.3,4
Of particular significance are approaches that furnish modifiable
and synthetically versatile allylic, homoallylic, propargylic, or
benzylic tertiary carbinols.3,4 Herein, we report methods for Al-
catalyzed asymmetric alkylation (AA) reactions of pyridyl-
substituted propargyl ketones with dialkylzinc reagents (Scheme
1). Enantiomerically enriched tertiary alcohols are obtained
through reactions promoted by easily accessible amino acid-
based catalysts. Enantiomerically enriched products, obtained
in up to >98% ee, bear a hydroxyl-substituted quaternary carbon
stereogenic center flanked by an alkyne and a pyridyl unit, a
combination that is found in biologically active molecules5 and
can be exploited for accessing heterocyclic organic molecules
that would otherwise be difficult to prepare (Scheme 1).
Molecules
Our focus on catalytic AA reactions of ynones stemmed from
several considerations:
(1) Au-,6 Cu-,7 and Pt-catalyzed8 reactions of pyridyl-
substituted propargyl alcohols, furnishing an assortment of useful
(4) For representative examples of catalytic enantioselective additions of
carbon-based nucleophiles to ketones, see: (a) Evans, D. A.; Ko-
zlowski, M. C.; Burgey, C. S.; MacMillan, D. W. J. Am. Chem. Soc.
1997, 119, 7893–7894. (b) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc.
1998, 120, 445–446. (c) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001,
123, 6195–6196. (d) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002,
124, 4233–4235. (e) Celina, G.; LaRochelle, L. K.; Walsh, P. J. J. Am.
Chem. Soc. 2002, 124, 10970–10971. (f) Yus, M.; Ramon, D.; Prieto,
O. Eur. J. Org. Chem. 2003, 2745–2748. (g) Wada, R.; Oisaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910–8911.
(h) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964–
8965. (i) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed.
2006, 45, 3353–3356. (j) Li, H.; Wang, B.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 732–733. (k) Lou, S.; Moquist, P. N.; Shaus, S. E.
J. Am. Chem. Soc. 2006, 128, 12660–12661. (l) Zhao, D.; Oisaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440–14441.
(m) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006, 128,
16448–16449. (n) Siewert, J.; Sandmann, R.; von Zezschwitz, P.
Angew. Chem., Int. Ed. 2007, 46, 7122–7124. (o) Hatano, M.;
Miyamoto, T.; Ishihara, K. Org. Lett. 2007, 9, 4535–4538.
(1) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christophers, J., Baro, A., Eds; Wiley-VCH: Weinheim,
2006.
(2) For examples of catalytic asymmetric protocols that deliver enantio-
merically enriched tertiary alcohols (non-propargylic) but are not
additions to ketones, see: (a) Gillingham, D. G.; Kataoka, O.; Garber,
S. B.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 12288–12290.
(b) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006,
45, 3353–3356. (c) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc.
2006, 128, 16448–16449. (d) Jung, B.; Hong, M. S.; Kang, S. H.
Angew. Chem., Int. Ed. 2007, 46, 2616–2618. (e) Zhao, Y.; Mitra,
A.; Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed. 2007,
46, 8471–8474.
(3) For a recent review on catalytic enantioslective additions to ketones,
see: Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873–
888.
9
9942 J. AM. CHEM. SOC. 2008, 130, 9942–9951
10.1021/ja802935w CCC: $40.75
2008 American Chemical Society

Alkylations of Pyridyl-Substituted Ynones
A R T I C L E S
Table 1. Screening of Chiral Ligands for Catalytic AA Reactions of
Propargyl Ketone 1a with Et2Zna
heterocyclic compounds, have recently been developed. The
utility of such methods would be elevated by the availability
of a catalytic asymmetric protocol that allows for synthesis of
the requisite substrates in high enantiomeric purity.
(2) The acetylene moiety of the tertiary propargyl alcohols
can be used to synthesize useful heterocyclic structures. For
example, alkyl and alkenyl (cis and trans) tertiary allylic
alcohols would be accessed through catalytic hydrogenation
procedures. Alternatively, deprotonation of a terminal alkyne
may be followed by treatment with a range of electrophiles.
(3) To the best of our knowledge, there are no existing
examples of catalytic AA reactions of pyridyl ketones with
alkylmetal reagents, and enantioselective additions of C-based
nucleophiles to ynones are relatively uncommon.9,10 It should
be noted that the significant majority of catalytic alkylations of
acyclic ketones involve methyl-substituted substrates,4,10,11
presumably to ensure maximum levels of enantioselectivity (due
to optimal size difference between carbonyl substituents).
Our goal was to investigate catalytic AA reactions of pyridyl
ynones through the use of readily accessible and easily
modifiable amino acid-based chiral ligands developed in these
laboratories.12 One class of reactions promoted in the presence
of the aforementioned ligands is catalytic enantioselective
additions of C-based nucleophiles to ketones,13 including Al-
catalyzed cyanide additions of aryl- and alkyl-substituted
unactivated ketones9a and Al-catalyzed AA reactions of R-ke-
toesters with dialkylzinc reagents.14
Results and Discussion
1. Catalytic Asymmetric Alkylation Reactions of Ynones
with Et2Zn. a. Identification of an Effective Chiral Ligand. We
began by probing the ability of several amino acid-based ligands
(5) For pyridyl-substituted tertiary propargyl alcohols that exhibit biologi-
cal activity, see: Starck, J.-P.; Talaga, P.; Que´re´, L.; Collart, P.;
Christophe, B.; Lo Brutto, P.; Jadot, S.; Chimmanada, D.; Zanda, M.;
Wagner, A.; Mioskowski, C.; Massingham, R.; Guyaux, M. Bioorg.
Med. Chem. 2006, 16, 373–377.
a All reactions were performed under a N2 atmosphere; see the
Supporting Information for experimental details. All catalytic alkylations
proceed to >98% conversion. b Enantioselectivities were determined by
chiral HPLC analysis; see the Supporting Information for details. nd )
not determined; abs. conf. ) absolute configuration of major product
enantiomer.
(6) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050–
12051.
(7) (a) Jansen, A.; Krause, N. Synthesis 2002, 1987–1992. (b) Jansen,
A.; Krause, N. Inorg. Chim. Acta 2006, 359, 1761–1766. (c) Yan, B.;
Zhou, Y.; Zhang, H.; Chen, J.; Liu, Y. J. Org. Chem. 2007, 72, 7783–
7786.
(8) Smith, C.; Bynnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett.
2007, 9, 1169–1171.
to catalyze the enantioselective addition of Et2Zn to ynone 1a
in the presence of Al(Oi-Pr)3, a combination formerly identified
as optimal in catalytic alkylations of R-ketoesters.14 Key findings
from initial studies are summarized in Table 1. All transforma-
(9) For catalytic enantioselective additions of C-based nucleophiles to
ynones, see: (a) Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2001, 41, 1009–1012. (b) Christensen,
C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
4875–4881. (c) Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki,
M. Angew. Chem., Int. Ed. 2003, 42, 5489–5492. (d) Tian, S-K.; Deng,
L. J. Am. Chem. Soc. 2003, 125, 9900–9901.
(12) (a) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 1996, 35,
1668–1671. (b) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Gleason,
J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121,
4284–4285. (c) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 755–756. (d) Porter, J. R.; Traverse, J. F.;
Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984–
985. (e) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2001, 40, 1456–1460. (f) Josephsohn,
N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126,
3734–3735. (g) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 4584–4585. (h) Kacprzynski, M. A.; Kazane,
S. A.; May, T. L.; Hoveyda, A. H. Org. Lett. 2007, 9, 3187–3190. (i)
Fu, P.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130,
5530–5541.
(10) For catalytic enantioselective additions of alkynyl metals to ketones,
see: (a) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895–2898.
(b) Saito, B.; Katsuki, T. Synlett 2004, 1557–1560. (c) Zhou, Y.; Wang,
R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004, 6,
4147–4149. (d) Liu, L.; Wang, R.; Kang, Y-F.; Chen, C.; Xu, Z-Q.;
Zhou, Y-F.; Ni, M.; Cai, H-Q.; Gong, M-Z. J. Org. Chem. 2005, 70,
1084–1086.
(11) For additional examples, see: (a) Casolari, S. J.; D’Addario, D.;
Tagliavini, E. Org. Lett. 1999, 1, 1061–1063. (b) Waltz, K. M.;
Gavinonis, J.; Walsh, P. J. Angew. Chem., Int. Ed. 2002, 41, 3697–
3699. (c) Prieto, O.; Ra`mon, D. J.; Yus, M. Tetrahedron: Asymmetry
2003, 14, 1955–1957. (d) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004,
126, 6538–6539. (e) Cunningham, A.; Mokal-Parekh, V.; Wilson, C.;
Woodward, S. Org. Biomol. Chem. 2004, 2, 741–748. (f) Teo, Y.-C.;
Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2743–2745. (g) Wadamoto,
M.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556–14557. (h)
Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006, 128,
12660–12661.
(13) For an example, see: Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2006, 128, 6532–6533.
(14) Wieland, L. C.; Deng, H.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 15453–15456.
9
J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9943

A R T I C L E S
Friel et al.
Table 2. Al-Catalyzed AA Reactions with Et2Zna
tions were performed in the presence of diethylphosphoramidate
(3), based on the positive effect of this additive on the efficiency
and enantioselectivity in the previously reported Al-catalyzed
process.15
The need for a particularly active chiral catalyst became clear
in the course of these initial investigations: in the absence of a
metal salt and a chiral ligand, even at -78 °C, the reaction of
Et2Zn to 1a proceeds readily to >98% conversion, affording
rac-2a within only 20 min. Moreover, we discovered that, in
addition to overcoming a facile uncatalyzed alkylation, the chiral
catalyst would have to compete effectively with a side reaction:
when Et2Zn is used with 50 mol % 3 (in the absence of an Al
salt and/or a chiral ligand), a nearly equal amount of the
corresponding secondary alcohol is generated, presumably as a
result of competitive hydride addition.
Thus, as depicted in entry 1 of Table 1, we established that,
when catalytic AA is performed with 5 mol % 4, a ligand
identified as optimal for related reactions of R-ketoesters,14
tertiary alcohol 2a is obtained cleanly in 75% ee without any
detectable amount of the undesired secondry propargyl alcohol
(>98% conv, 20 min, -78 °C). Chiral ligands bearing a single
amino acid does not give rise to effective catalysts (entry 2).
The observation that Schiff base 6 (entry 3), consisting of two
readily available and inexpensive amino acids (both antipodes),
affords appreciable asymmetric induction (59% ee) was en-
couraging, leading us to probe the activity of 7-9 (entries 4-6,
Table 1). The low selectivities obtained with 7 and 8 illustrate
that two chiral amino acid residues are required for the Al-
based catalyst to be able to compete effectively with uncatalyzed
Et2Zn addition.
mol
%
conv
(%)b
yield
ee
conv
(%)b
yield
(%)c
ee
(%)d
entry
R
(%)c (%)d
1
2
3
4
5
6
7
8
C6H5
a
b
b
c
d
e
f
5
5
>98 61
>98 64
95 >98 80 >98
82 >98 68 89
o-MeC6H4
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-OMeC6H4
p-CF3C6H4
p-CF3C6H4
p-IC6H4
p,m-Cl2C6H3
o-BrC6H4
o-BrC6H4
3-thiophene
n-hex
10 >98 65
10 >98 70
10 >98 68
10 >98 64
89 >98 65 >98
95 >98 62 >98
92 >98 74 >98
96 >98 67 >98
81 >98 80 >98
93 >98 83 >98
80 >98 72 >98
81 >98 84 >98
5
>98 80
f
10 >98 83
10 >98 58
10 >98 54
9
g
h
i
i
j
k
l
m
10
11
12
13
14
15
16
5
>98 46
77 >98 51
92
10 >98 46
10 >98 56
10
10
84 >98 87 >98
93 >98 77 >98
79 63
72 67
75 >98 73
98
Cy
(i-Pr)3Si
78 >98 74 >98
10 >98 74
85 >98 84 >98
a All reactions were performed under a N2 atmosphere; see the
Supporting Information for experimental details. b Determined through
analysis of 400 MHz 1H NMR spectra. c Yields of products after
purification. d Enantioselectivities were determined by chiral HPLC
analysis; see the Supporting Information for details.
b. Catalytic AA with Et2Zn. Through the use of chiral ligand
10c and Al(Oi-Pr)3, a wide range of pyridyl-substituted ynones
can be efficiently alkylated with Et2Zn (Table 2).17 The
following points regarding the data in Table 2 are noteworthy:
The catalytic AA reaction in the presence of ligand 9 (entry
6) proved critical for several reasons:
(1) The preferential formation of the opposite enantiomer,
compared to reactions with ligands that bear two L-amino acids
(e.g., 4 in entry 1 and 6 in entry 3), indicates that it is the AA2
unit (the C-terminus amino acid) that controls the identity of
the major isomer.
(1) Reactions furnish products with high enantioselectivity
in the presence of 5 mol % catalyst (e.g., entries 1, 2, 7, and 11
of Table 2). In many cases, however, asymmetric induction is
enhanced when 10 mol % loading is utilized (compare entries
2-3 and 11-12). Lower amounts of catalyst have a detrimental
effect on selectivity in transformations that involve alkyl-
substituted ynones; Al-catalyzed AA of 1k (entry 14, Table 2)
thus affords 2k in 61% ee, along with 10-15% of the racemic
secondary alcohol, when 5 mol % catalyst is used. Presumably,
catalytic alkylations of less reactive substrates do not effectively
compete with the aforementioned uncatalyzed and facile addition
of Et2Zn.
(2) Catalytic AA reactions performed in the absence dieth-
ylphosphoramidate 3 proceed with lower enantioselectivity (see
data in Table 2). In cases where the alkyne is alkyl-substituted,
the influence of this additive is especially noticeable. For
example, in alkylations of ynones 1k and 1l (entries 14 and 15,
Table 2), enantioselectivities are improved from 75% and 78%
ee to 98% and >98% ee, respectively. In most cases, purified
products are isolated in higher yields when 3 is used.
(2) Since 9, a ligand that bears D- and L-antipodes of two
inexpensive amino acids, furnishes tertiary propargyl alcohol
2a in 70% ee (entry 6), we focused our efforts on the ligand’s
C- and N-termini to establish whether alteration of the steric
and electronic attributes of these segments would result in
improvements in enantioselection.16 Replacement of the n-butyl
of the C-terminus amide with a phenyl group (10a, entry 7)
leads to a significant change in enantioselectivity (95% vs 70%
ee in entry 6). Such a variation offers the opportunity for
modification of the electronic attributes of this part of the chiral
ligand, which resulted in further improvements in enantiose-
lectivity: incorporation of the corresponding p-CF3 (10c, entry
9) affords 2a with exceptional enantioselectivity (>98% ee by
chiral HPLC analysis).
(3) Inclusion of a p-CF3-phenyl group at the C-terminus of a
ligand that bears two L-amino acids does not render it competi-
tive with 10c; such a ligand affords (R)-2a in only 65-75% ee
(vs (S)-2a formed in >98% ee with 10c).
(3) Alkynes bearing electron-deficient (entries 7-12, Table
2), electron-rich (entry 6), and sterically demanding aryl (entries
2 and 3) as well as alkyl (entries 14 and 15), heterocyclic (entry
13), and silyl (entry 16) substituents undergo facile alkylations
in good yields and in up to >98% ee.
(15) For a review on the effect of additives in asymmetric catalysis, see:
Vogl, E. M.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999,
38, 1570–1577.
(16) For representative cases, where C-terminus modification in this class
of chiral ligands has led to substantial improvement in efficiency and/
or enantioselectivity, see: (a) Josephsohn, N. S.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4018–4019. (b)
Mampreian, D. M.; Hoveyda, A. H. Org. Lett. 2004, 6, 2829–2832.
(17) The identity of the major enantiomers in reactions with Et2Zn is based
on an X-ray crystal structure obtained for 2g (entry 9, Table 2). See
the Supporting Information for details.
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9944 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Alkylations of Pyridyl-Substituted Ynones
A R T I C L E S
Table 3. Screening of Chiral Ligands for Catalytic AA Reactions of
Ketone 1a with Me2Zna
(4) In certain instances, in the absence of 3, substantial
amounts of the undesired secondary alcohol are obtained (<2%
ee). As an example, in reactions shown in entries 10-13,
15-20% of the reduced product is isolated in the absence of
the additive.
2. Catalytic Asymmetric Alkylation Reactions with
Me2Zn. a. Identification of an Effective Chiral Ligand. Next,
we turned our attention to transformations with Me2Zn. This
change can result in significant variations in the reaction regime;
as will be illustrated below, such proved to be the case here.
Thus, the chiral ligand identified as optimal for additions with
Et2Zn is not nearly as effective with this less reactive dialkylzinc
reagent. As shown in eq 1, there is <2% conversion for
alkylation of 1a in the presence of ligand 10c (at -78 °C). It is
only at -30 °C that appreciable conversion is observed, albeit
resulting in the formation of racemic 11a (<2% ee). An
unexpected observation in these preliminary investigations is
also depicted in eq 1: in contrast to additions involving Et2Zn,
catalytic alkylation of 1a with Me2Zn proceeds with higher
enantioselectivity in the absence of diethylphosphoramidate 3
(23% ee vs <2% ee). These findings suggested that an
alternative ligand had to be identified for efficient Al-catalyzed
alkylations with Me2Zn and that the effect of 3 as an additive
would have to be re-evaluated.
A number of amino acid-based Schiff bases were thus
examined. Selected data from these studies are summarized in
Table 3. These initial studies were carried out in the presence
of additive 3 (see below for additional detail). The findings in
entries 1-4 of Table 3 show that, in contrast to catalytic AA
reactions involving Et2Zn, ligands that bear two amino acid
moieties deliver appreciable activity (68-73% conv after 24 h
at -30 °C), but the desired tertiary alcohol (11a) is obtained
either in the racemic form or with low selectivity (<10% ee).
Ligands containing a single amino acid unit give rise to
significantly more discriminating catalysts (entries 5 and 6, Table
3). In the presence of Schiff base 5 (entry 5), bearing a valine
unit, reaction proceeds with similar efficiency (67% conv) to
furnish 11a in 14% ee. When the amino acid moiety is changed
to phenylalanine (ligand 12, entry 6), ketone alkylation takes
place with similar efficiency (77% conv), but 11a is isolated
with improved enantiopurity (65% ee). Further screening
studies18 led us to establish that the derived benzylcysteine 13a,
which contains a 3,5-dichlorosalicyl Schiff base, is more
effective: Al-catalyzed AA proceeds to 91% conversion within
24 h to furnish 11a in 73% ee. Alteration of the substituents at
the C-terminus only leads to lowering of catalytic activity and/
or asymmetric induction. Noteworthy is the significantly reduced
degree of enantioselectivity observed with ligand 13e (entry 11,
Table 3), which bears a p-CF3-phenylamide terminus (64% vs
91% conversion and 42% vs 73% ee compared to 13a); this
observation provides an additional distinction between reactions
of the two dialkylzinc reagents (entries 6 and 9 of Table 1).
a All reactions were performed under a N2 atmosphere; see the
Supporting Information for experimental details. b Determined through
analysis of 400 MHz 1H NMR spectra. c Enantioselectivities were
determined by chiral HPLC analysis; see the Supporting Information for
details. nd ) not determined.
Subsequently, we established that the related chiral ligand 14,
prepared from the less expensive non-halogenated salicyl
aldehyde, performs at a similar level of efficiency (entry 12,
Table 3; 89% conv after 24 h and 70% ee).
b. Catalytic AA Reactions with Me2Zn. The initial studies
summarized in eq 1 indicated that, unlike reactions with Et2Zn,
catalytic alkylations involving Me2Zn may proceed with higher
selectivity in the absence of diethylphosphoramidate. Accord-
ingly, we examined the Al-catalyzed enantioselective synthesis
of tertiary propargyl alcohol 11a in the absence of this additive.
As illustrated in entry 1 of Table 4, catalytic AA proceeds
readily to afford 11a in 95% ee (vs 70% ee in the presence of
3) and 74% yield after silica gel purification.19 A variety of
pyridyl-substituted ynones containing electron-donating (entry
2, Table 4), electron-withdrawing (entries 3-6, Table 4),
heterocyclic (entry 7, Table 4), and n-alkyl (entry 8, Table 4)
(18) See the Supporting Information for details of ligand screening studies.
9
J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9945

A R T I C L E S
Friel et al.
Table 4. Al-Catalyzed AA Reactions with Me2Zna
and 10a,b, illustrated in Table 1). Thus, catalytic AA with chiral
ligand 14, performed in the absence of 3, proceeds somewhat
more efficiently and enantioselectively (25-30% ee vs 15-20%
ee) even for reactions that involve Et2Zn. Such findings suggest
that the effectiveness of the additive is catalyst-dependent: it is
when a chiral ligand bearing two amino acid moieties (with
Et2Zn) is used that the presence of diethylphosphoramidate 3
is advantageous.
entry
R
conv (%)b
yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
C6H5
a
e
f
g
h
i
j
k
m
>98
>98
>98
>98
>98
>98
>98
>98
>98
74
77
70
58
53
57
74
59
65
95
96
87
79
95
96
91
89
57e
p-OMeC6H4
p-CF3C6H4
p-IC6H4
p,m-Cl2C6H3
o-BrC6H4
3-thiophene
n-hex
(i-Pr)3Si
a All reactions were performed under a N2 atmosphere; see the
Supporting Information for experimental details. b Determined through
analysis of 400 MHz 1H NMR spectra. c Yields of products after silica
gel purification. d Enantioselectivities were determined by chiral HPLC
analysis; see the Supporting Information for details. e Reaction
performed at -50 °C with ligand 15.
substituents can be catalytically alkylated with high selectivity
(79-96% ee).
3. Catalyst Recycling and Matters of Practicality. Enantios-
lective alkylations can be performed on a useful laboratory scale,
as the example in eq 3 illustrates (∼0.8 g of ynone 1m).
Terminal alkyne 17, which cannot be accessed through direct
alkylation,22 is obtained in 92% ee and 84% overall yield
(catalytic AA and removal of the silyl group).
Alkylation of silyl-substituted ynone 1m (entry 9, Table 4),
performed at -50 °C and requiring ligand 15 for optimized
selectivity, proceeds with moderate enantioselectivity. Reaction
of 1m in the presence of ligand 14 (at -50 °C) affords 11m in
only 22% ee and 45% yield. Ynone 1m, at -30 °C, undergoes
a particularly facile alkylation in the absence of a chiral ligand
and without an Al salt present. Such uncatalyzed processes20
occur with alkyl-substituted ynones such as 1k, but at a slower
rate and to a lesser degree with aryl-substituted alkynes.21 The
lower selectivity for the formation of silyl-substituted 11m
serves as an additional point of contrast with reactions involving
Et2Zn, which can be used to alkylate 1m in >98% ee (85% ee
Several points regarding the representative transformation in
eq 3 merit specific mention:
(1) Al(Oi-Pr)3 can be used easily only when it is freshly
distilled and exists as a soluble (in toluene) oil, but it solidifies
upon exposure to air. In contrast, Al(Os-Bu)3 persists as a
toluene-soluble oil, even when exposed to air.23 As a result,
for reactions run on relatively larger scale, use of commercially
in the absence of additive 3; see entry 16, Table 2).
The difference in the two classes of catalytic alkylations is
further highlighted by the findings shown in eq 2. In the presence
of 15 mol % ligand 14, optimal for reactions of Me2Zn, and 50
mol % diethylphosphoramidate 3, alkylation of 1a with Et2Zn
proceeds to 82% conversion to furnish 2a in only 15-20% ee
with an equal amount of secondary alcohol rac-16; <2% of
rac-16 is generated when ligand 10c is used (as well as 6-9
(22) Terminal alkynes undergo facile uncatalyzed alkylation under the
reaction conditions (-78 °C for Et2Zn and-30 °C for Me2Zn), even
in the absence of an Al salt, to afford racemic tertiary propargylic
alcohols.
(23) Al(Oi-Pr)3 (purchased from Strem) is a white powder with a tetrameric
structure and is insoluble in toluene, which is the solvent used for
Al-catalyzed AA reactions described in this study. After distillation,
however, Al(Oi-Pr)3 exists as a readily soluble clear liquid. The oil
readily turns to a white powder when exposed to air or after standing
for longer periods of time (under nitrogen or vacuum). (See: Shiner,
V. J., Jr.; Whittaker, D.; Fernandez, V. P. J. Am. Chem. Soc. 1963,
85, 2318–2322) It is the oil (distilled) form of Al(Oi-Pr)3 that is
effectively used for catalytic alkylations. In contrast, Al(Os-Bu)3 is
an oil and remains as such in air; it is thus a more practical salt for
use, particularly for transformations performed on a relatively large
scale (e.g., gram quantities of ketone substrate). Al(Os-Bu)3 should
be stored under nitrogen, since, after extended periods of time
(months), it turns into a solid, presumably due to the formation of
aluminum oxides.
(19) The identity of the major enantiomers in reactions with Me2Zn is based
on an X-ray crystal (Cu irradiation) structure obtained for 11a (entry
1, Table 4). See the Supporting Information for details.
(20) Although initial screening studies were performed with 5 mol %
catalyst loading (see Table 3), we subsequently established that larger
amounts of catalyst (see Table 4) generally deliver improved levels
of enantioselectivity, presumably due to minimization of nonselective
(uncatalyzed) alkylations.
(21) The amount of uncatalyzed (background) reaction depends on the
substrate and likely its inherent electrophilicity. For instance, there is
20-25% conversion with p-CF3-aryl ketone 1f (entry 3, Table 4) under
otherwise identical conditions (-30 °C) but in the absence of the chiral
ligand.
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9946 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Alkylations of Pyridyl-Substituted Ynones
A R T I C L E S
available Al(Os-Bu)3 is preferred. Under such conditions, Al-
catalyzed AA can be carried out on a bench top under inert
atmosphere without resorting to rigorous protocols or glovebox
techniques.
(2) The chiral ligand can be recovered after the reaction in
71-87% yield after purification and reused for at least four
additional transformations without diminution in efficiency or
product enantiopurity.
secondary alcohols. The pyridyl-substituted tertiary alcohols,
now available in high enantiomeric purity, through a subsequent
and facile Cu-catalyzed transformation,26 can be converted to
synthetically versatile bicyclic systems that contain a quaternary
R-amino carbonyl group. Representative examples are illustrated
in Scheme 3. Treatment of enantiomerically pure tertiary
propargyl alcohol 2a with 5 mol % CuI (82 °C) results in
complete conversion (>98%) within 2 h, providing 26 in 80%
yield after chromatography. Synthesis of bicycle 27 (78% yield
after purification) represents a reaction of an enantiomerically
pure substrate that bears a modified pyridyl group (see 22,
Scheme 2). Catalytic cyclization of terminal alkyne 17 (see eq
3) affords 28 at a slower rate compared to the aforementioned
two processes, presumably because the developing positive
charge ꢀ to the developing carbonyl unit is less stabilized due
to the lower degree of substitution. Nonetheless, the desired
bicycle is obtained in 56% yield after silica gel chromatography.
Cu-catalyzed reaction of alkyl-substituted tertiary propargyl
alcohol 2k (see entry 14, Table 2) proceeds less readily than
that of the unsubstituted derivative (17 f 28).
4. Synthesis and Catalytic AA Reactions of Modified
Pyridyl Substrates and Other Functionalization Procedures.
a. Synthesis and Al-Catalyzed AA Reactions of Substrates
Bearing Modified Pyridines. As illustrated below, one of the
advantages of the present method is that the alkyne and the pyridyl
group residing within AA products offer opportunities for useful
functionalization procedures. Beyond changes in the substituents
of the ynones, demonstrated above, substrates with different pyridyl
groups can be used in the Al-catalyzed AA reactions. The synthesis
route illustrated in Scheme 2, involving the four-step synthesis of
4-methoxy-substituted pyridine 21,24 is representative and dem-
onstrates the feasibility of structural modifications at the pyridyl
site. Thus, tertiary propargyl alcohols 22-24,25 accessed in 77%
to >98% ee and in 53-88% yield (under conditions shown for
Tables 2 and 4), are obtained through enantioselective alkylations
of substrates with modified pyridines.
Scheme 3. Functionalization of Pyridyl-Substituted Tertiary
Carbinols: Application to Cu-Catalyzed Enantioselective Synthesis
of Indolizinones
b. Functionalizations Involving the Pyridyl Groups of
Products. A number of recent disclosures have involved catalytic
(non-asymmetric) transformations of pyridyl-substituted prop-
argyl alcohols to the corresponding N-fused bicyclic structures
(Scheme 3). Au-,6 Cu-,7 and Pt-based8 catalysts have been
reported to promote such processes with various levels of
efficiency; the majority of the cases involve reactions of
Scheme 2. Synthesis and Al-Catalyzed AA of Substrates with a
Modified Pyridine
A critical point regarding the Cu-catalyzed reactions relates
to the retention of the stereochemical integrity of the tertiary
carbinol sites in the cyclization process. With the availability
of enantiomerically enriched tertiary propragyl alcohols, such
issues can be investigated. Formation of enantiomerically pure
26 and 27 (Scheme 3) illustrates that, in cases where catalytic
cyclization is facile (reaction proceeds to >98% conversion
within 2 h), there is complete retention of stereochemistry. When
the Cu-catalyzed process is relatively sluggish, however, some
enantiomeric purity is lost. Bicyclic amide 28 is thus obtained
in 96% ee from a sample of 2m that is isolated in >98% ee,
and the slowest-forming alkyl-substituted 29 is generated in 80%
ee from a substrate (11k) which is prepared in 89% ee. It is
plausible that, with the slower cyclizations, the Cu-alkyne
complex, serving as an intermediate in the catalytic cycle,
coordinates to the neighboring Lewis basic hydroxyl group and
facilitates epimerization at the carbinol center by a C-O bond
dissociation/re-formation process.
(24) The Reissert-Henze cyanation of pyridine oxides in Scheme 2 is based
on the following reported procedure: Fife, W. J. Org. Chem. 1983,
48, 1375–1377.
(25) Pyridyl ketone 24 is prepared from the commercially available
carboxylic acid (via the derived Weinreb amide and subsequent
alkylation with the alkynyl lithium).
(26) Attempts to promote similar cyclizations with a number of alkylation
products (including alkyl-substituted 2l) in the presence of 15-30 mol
% PtCl2 (see ref 10) resulted in generation of complex mixtures of
products.
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J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9947

A R T I C L E S
Friel et al.
Scheme 4. Representative Functionalizations of Alkyne Group of
the Catalytic AA Products
Scheme 5. Application to Enantioselective Synthesis of
Tetrasubstituted Allenes
tuted allene 35 in 74% yield;29 synthesis of 36, involving the
reaction of tert-butyllithium, provides an additional example.
In both examples in Scheme 5, there is limited loss of
enantiopurity. Similar observations have been disclosed for
transformations that involve enantiomerically enriched second-
ary propargyl alcohols; electron-transfer processes involving the
allene product and the cuprate reagents have been suggested to
rationalize such observations.7c Access to nonracemic tertiary
propargyl alcohols thus leads to the generation of fully
substituted allenes in high enantiomeric purity.30
5. Mechanistic Considerations. The presence of the pyridyl
unit is critical to effective alkylation: there is <2% conversion
when aryl ketone 37 and furyl ketone 38 are used as substrates
under the conditions used for reactions with Et2Zn described in
Table 2. These observations underline the importance of two-
point chelation, involving Lewis acidic Al and the Lewis basic
c. Functionalizations Involving the Alkyne Groups of AA
Products. The alkyne unit of the enantiomerically enriched
products can be readily hydrogenated to afford the corresponding
fully saturated alkyl-substituted tertiary alcohols without com-
plications from the relatively sensitive tertiary benzylic alcohol;
synthesis of 30 in 84% yield through a simple Pd-catalyzed
hydrogenation is representative (Scheme 4). Similarly, hydro-
genation of tertiary carbinol 2a in the presence of 10 mol %
Pd(CaCO3) results in stereoselective reduction of the alkyne,
furnishing allylic alcohol 31 as a 10:1 mixture of cis:trans
isomers and in 87% yield (Scheme 4). Through treatment of
11a with Red-Al,27 the derived trans tertiary alcohol 32 is
obtained as a single alkene isomer (>98% trans) and in 71%
yield after silica gel chromatography.
carbonyl and N atom of the pyridine.
a. Reactions with Et2Zn. Al-catalyzed AA reactions of Et2Zn
with ligands that bear an L-valine and a L-phenylalanine (or
vice versa) can be explained by the intermediacy of I-III,
illustrated in Figure 1. The Lewis basic amide at the C-terminus
of the ligand chelates with and enhances the nucleophilicity of
the alkylzinc reagent31 toward addition to a substrate molecule
(I and II), and the Lewis acidic Al associates with and activates
the substrate molecule, which undergoes enantioselective alky-
It was mentioned previously that silyl-substituted products
offer access to enantiomerically enriched terminal alkynes,
which can be alkylated to provide functionalities that can be
used for further structural modification. The desilylation/
alkylation sequence illustrated in Scheme 4, leading to the
conversion of 2m to 33, which is a potential substrate for a
number of enyne cyclization reactions,28 illustrates this point.
The stereochemically defined tertiary propargyl alcohol
presents numerous opportunities for conversion of the AA
products to a wide variety of compounds that are otherwise
difficult to access in high enantiomeric purity. A representative
case is illustrated in Scheme 5. Treatment of acetate 34, obtained
in quantitative yield from enantiomerically enriched 2a, with
cyclopentylmagnesium chloride in the presence of CuCN at -40
°C leads to the formation of enantiomerically pure tetrasubsti-
(29) For other methods that furnish enantiomerically enriched tetrasubsti-
tuted allenes, see: (a) Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett.
2003, 6, 305–307. (b) Miura, T.; Shimada, M.; Ku, S-Y.; Tamai, T.;
Murakami, M. Angew. Chem., Int. Ed. 2007, 46, 7101–7103. For a
protocol for synthesis of Ti-substituted tetrasubstituted allenes, see:
(c) Okamoto, S.; An, D. K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551–
4554.
(30) For reviews on stereoselective synthesis of allenes, see: (a) Krause,
N.; Hoffman-Ro¨der, A. Tetrahedron 2004, 60, 11671–11694. (b)
Miesch, M. Synthesis 2004, 746–752. (c) Brummond, K. M.; De
Forrest, J. Synthesis 2007, 795–818. (d) For allene-containing natural
products or biologically active molecules, see Hoffman-Ro¨der, A.;
Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196–1216.
(31) For a detailed discussion of Lewis base activation of Lewis acids,
see: (a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008,
47, 1560–1638. For recent applications of this concept toward
development of new chiral catalysts and catalytic enantioselective
protocols from these laboratories, see: (b) Reference 14. (c) Zhao,
Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443,
67–70. (d) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128,
15604–15605.
(27) Corey, E. J.; Katzellenbogen, J. A.; Posner, G. H. J. Am. Chem. Soc.
1967, 89, 4245–4247.
(28) For recent examples of enyne cyclization reactions, see: (a) Pearson,
A. J.; Dubbert, R. A. Organometallics 1994, 13, 1656–1661. (b)
Negishi, E-i.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum,
F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111,
3336–3346. (c) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am.
Chem. Soc. 2004, 126, 8654–8655. (d) Kim, H.; Lee, C. J. Am. Chem.
Soc. 2005, 127, 10180–10181. (e) Jime´nez-Nu´n˜ez, E.; Echevarren,
A. M. Chem. Commun. 2007, 333–346.
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9948 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Alkylations of Pyridyl-Substituted Ynones
A R T I C L E S
Figure 1. Mechanistic models for Al-catalyzed AA reactions with Et2Zn based on calculations performed at the MMFF94 level in Spartan.
lation.32 The competing mode of addition is represented in I-III
(dotted arrows, Figure 1): the alkylmetal adds to the bound
substrate without activation by the chiral ligand’s amide
terminus. It is unclear, however, whether it is the cationic
complex I or the neutral complex II (or III), that promotes
alkylation.
carbonyl cannot be directed to add to the Al-bound pyridyl
ketone due to geometric constraints.
Molecular mechanics calculations35 suggest that a Zn bridge
consisting of the Lewis basic phosphoramidate (additive) with
the carbonyl of the ligand’s C-terminus leads to a high degree
of rigidity in complexes IV and V, resulting in the enhanced
enantioselectivity observed for L,D-dipeptide 10c versus an L,L-
ligand such as 6 (see entry 3, Table 1). The elevated enanti-
oselectivity obtained through the use of ligands that contain an
arylamide C-terminus (e.g., 10a-c in entries 7-9 of Table 1)
vs alkylamides such as 9 (entry 6, Table 1) may originate from
the more acidic amide proton which undergoes deprotonation,
thus increasing the Lewis basicity of the amide carbonyl, which
in turn helps to strengthen the proposed Zn bridge.
In all cases (I-III),33 we suggest that the strongly Lewis
basic phosphoramidate additive, by replacing an isopropoxy
ligand, increases Al Lewis acidity31 and catalytic activity.
Activation of the Al center by the phosphoramidate is identical
in nature to the interaction involving amide carbonyl interaction
with the dialkylzinc reagent. Modeling studies indicate that a
second molecule of phosphoramidate might interact with the
amide-bound alkylzinc reagent (III, Figure 1), further elevating
Zn Lewis acidity34 as well as alkylmetal nucleophilicity. Such
considerations offer a rationale for the need for the presence of
relatively significant amounts of the Lewis basic additive (50
mol %).
TwoadditionalpointsregardingcomplexesI-Varenoteworthy:
(1) Coordination of the phosphoramidate additive (3) at the
apical position, anti to the i-Pr substituent of the AA1 moiety
(valine), is likely due to minimization of unfavorable steric
interactions. Such mode of phosphoramidate association deter-
mines the manner in which the pyridyl ynone binds to the Al
center, which in turn, as is discussed below, establishes whether
the chiral ligand can participate in directed alkylation (delivery
of the dialkylzinc by the Lewis basic amide at the C-terminus).
(2) The proposed function of the phosphoramidate additive,15
particularly its role to provide structural rigidity through Zn
chelation in complexes IV and V, finds support in the data
summarized in Table 5. Thus, although use of Me2NP(O)(OEt)2
(38; entry 2, Table 5) leads to complete conversion, 2k is
obtained in only 25% ee (vs 98% ee with H2NP(O)(OEt)2, entry
1). This difference in enantioselectivity may be attributed to
the absence of a Zn bridge as a result of the presence of the
alkylated phosphoramidate (additive cannot participate in ligand
exchange with an isopropoxyaluminum), giving rise to a
complex of reduced structural rigidity where the two enan-
tiotopic faces of the bound carbonyl are less effectively
differentiated. The diminution in enantioselectivity versus that
In contrast to the transformations promoted by L,L-dipeptides,
catalytic AA reactions with chiral ligands that bear an L-valine
and a D-phenylalanine (or vice versa) may proceed through
complexes IV and/or V (Figure 1); the previously favored (with
L,L-ligands in I-III) diastereotopic face is now blocked by the
substituent of the AA2 moiety, thus favoring the nondirected
mode of addition and causing a reversal in the sense of
enantioselective alkylation. The proposed scenario is consistent
with the finding that the absolute stereochemistry of the AA
product is predicated on the identity of the chiral ligand’s AA2
moiety (see Table 1 and the accompanying discussion). Ex-
amination of molecular models indicates that, in ligands that
carry an L-valine and a D-phenylalanine (or vice versa; see IV
and V), the diethylzinc coordinated to the AA2 (phenylalanine)
(32) (a) Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2001, 123, 11594–11599. (b) Carswell, E. L.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2006, 45,
7230–7233.
(33) For a recent review regarding bifunctional chiral catalysis, see: Ma,
J.-A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566–4583.
(34) Theoretical studies (HF and B3LYP level of theory) illustrate that
chelation of TMEDA with Me2Zn causes an increase in the positive
charge on Zn (qZn ) +1.247 to +1.364); see: Weston, J. Organome-
tallics 2001, 20, 713–720.
(35) All structures were minimized through the use of MMFF94 method,
as supplied by Spartan ’04, Wavefuncton, Inc. Irvine, CA. Merck
Molecular Force Field 94 was selected due to its ability to handle
peptide bonds with reasonable accuracy.
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J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9949

A R T I C L E S
Friel et al.
through reaction via complexes VI and/or VII.38 The adverse
effect of 3 in reactions with Me2Zn may be attributed to the
facilitation of the noncatalyzed process by this additive. Such
an effect is perhaps absent with processes involving Et2Zn, as
such transformations can be performed at -78 °C (vs -30 °C
for Me2Zn); at lower reaction temperatures, there may be
minimal activation of Et2Zn by 3 or, as suggested above, the
resulting complex may not be involved in alkylation due to steric
factors. The L,D-ligand 10c, effective for AA reactions with
Et2Zn, does not promote enantioselective additions of Me2Zn
since, in the absence of phosphoramidate additive and the Zn-
bridged complexes, differentiation of the diastereotopic faces
of the catalyst-bound substrate cannot be achieved.
Table 5. Effect of Additive Structure on Catalytic AA Reactions
with Et2Zna
entry
additive
conv (%)b
ee (%)c
1
2
3
4
H2NP(O)(OEt)2 (3)
Me2NP(O)(OEt)2 (38)
H2NP(O)(Oi-Pr)2 (39)
Ph3P-O
>98
>98
77
98
25
85
30
85
a All reactions were performed under a N2 atmosphere. b Determined
through analysis of 400 MHz 1H NMR spectra. c Enantioselectivities
were determined by chiral HPLC analysis.
Conclusions
We have developed protocols for catalytic enantioselective
synthesis of tertiary propargyl alcohols bearing a pyridyl
substituent through Al-catalyzed alkylations with dialkylzinc
reagents. Chiral ligands can be prepared readily on gram-scale,
and the requisite substrates are accessible in no more than four
steps. The simplicity with which the present class of ligands
can be structurally modified has been exploited in identifying
the optimal chiral catalysts furnishing the highest possible level
of enantioselectivity in reactions involving Et2Zn and Me2Zn
as alkylating agents.
Figure 2. Model for Al-catalyzed AA reactions with Me2Zn based on
The protocols outlined herein furnish enantiomerically en-
riched products that contain a quaternary carbon stereogenic
center bearing three highly versatile substituents: an alcohol, a
pyridine, and an alkyne. As a result, a wide range of function-
alization procedures can be used to prepare small organic
molecules of high enantiomeric purity that would otherwise be
far more difficult to access. Transformation of the alkylation
product to bicyclic amide by a Cu-catalyzed process that
converts a tertiary carbinol to an N-substituted quaternary carbon
stereogenic center is a noteworthy example. Moreover, the
accessibility of tertiary propargyl alcohols by catalytic asym-
metric alkylation of ynones allows for the synthesis of enan-
tiomerically enriched tetrasubstituted allenes through Cu-
catalyzed allylic alkylation of the derived tertiary acetates by
Li-based or Grignard reagents.
calculations performed at the MMFF94 level in Spartan.
observed when an additive is not used (25% ee in entry 2, Table
5, vs 75% ee in entry 14, Table 2) may be due to Lewis base
activation of unbound dialkylzinc, culminating in substantially
more competitive uncatalyzed alkylation rates. Diisopropy-
lphosphoramidate 39 (entry 3, Table 5) can participate in the
formation of a Zn bridge, but perhaps less efficiently than 3
(entry 1, Table 5) because of the larger alkoxy groups (i-PrO
vs EtO). The low enantioselectivity observed when triph-
enylphosphine oxide is used as the additive (entry 4, Table 5)
is likely based on reasons similar to those outlined above for
phosphoramidate 38.
Catalytic AA reactions in entries 3 and 4 of Table 5 do not
proceed to >98% conversion, in spite of facile and complete
alkylation with Et2Zn, even in the absence of an Al salt or chiral
ligand. This difference in reactivity may suggest that the Lewis
basic additives might associate with the dialkylzinc reagent (in
addition to the Al center), as suggested previously (see III,
Figure 1), giving rise to a Et2Zn·phosphoramidate complex that
is significantly bulkier; this, in turn, results in diminished
alkylation rates in spite of the (possibly) enhanced alkylmetal
nucleophilicity. The involvement of a sterically demanding
Et2Zn·3 complex would result in an increase in enantioselec-
tivity when reactions proceed through complex IV or V, where
stereocontrol depends largely on steric blockage of one face of
the ketone substrate.
In spite of the advances described above, a number of
significant objectives remain to be addressed. Identification of
chiral catalysts that allow for alkylations with a wider range of
alkylating agents and at lower catalyst loadings is one goal of
(36) It should be noted that the proposal that π-π interactions give rise to
the observed enantioselectivities is not based on calculations, since
intermolecular aromatic π-π stacking interactions have not been
parameterized in MMFF94 ( Halgren, T. A. J. Comput. Chem. 1996,
17, 490–519). Attempts at performing calculations at higher levels of
theory proved prohibitive due to the large size of the complexes.
(37) For reviews of π-stacking interactions in organic synthesis, see: (a)
Jones, G. B.; Chapman, B. J. Synthesis 1994, 475–497. (b) Jones, G. B.
Tetrahedron 2001, 57, 7999–8016. For recent examples where
π-stacking interactions are proposed to account for the stereochemical
outcome of catalytic asymmetric reactions, see: (c) Ma, L.; Jiao, P.;
Zhang, Q.; Xu, J. Tetrahedron: Asymmetry 2005, 16, 3718–3734. (d)
Jiang, H.; Birman, V. B. Org. Lett. 2005, 7, 3445–3447. (e) Bisai, A.;
Singh, V. K. Org. Lett. 2006, 8, 2405–2408. (f) Ginorta, S. K.; Singh,
V. K. Org. Biomol. Chem. 2006, 4, 4370–4374. (g) Ma, L.; Jiao, P.;
Zhang, Q.; Du, D-M.; Xu, J. Tetrahedron: Asymmetry 2007, 18, 878–
884. (h) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am.
Chem. Soc. 2007, 129, 6756–6764.
b. Reactions with Me2Zn. The models that account for
enantioselective AA reactions with Me2Zn are illustrated in
Figure 2 (VI and VII). Calculations and examination of
molecular models indicate that the requirement for the presence
of an aryl-containing amino acid moiety within the chiral ligand
(see entries 6-12, Table 3) is due to the structural organization
gained through a π-stacking interaction36 involving the electron-
deficient pyridyl ring of the Al-bound substrate.37 Such π-π
association can inhibit addition from one face of the activated
ketone, leading to selective generation of one enantiomer
(38) Such π-π interactions are expected to remain operative in toluene,
which is a molecule with significantly lower ability to interrupt such
associations compared to benzene. This difference manifests itself in
the substantial difference in the respective melting points of these two
aromatic molecules (benzene mp ) +5.5 °C; toluene mp )-93 °C).
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9950 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Alkylations of Pyridyl-Substituted Ynones
A R T I C L E S
grateful to Ms. Kyoko Mandai (Boston College), Mr. Steve
Malcolmson (Boston College), Dr. Richard Staples (Harvard
University and Michigan State University), and Dr. Peter Mu¨ller
(Massachusetts Institute of Technology) for valuable assistance
regarding the X-ray structures. The X-ray facility at Boston College
is supported by Schering-Plough. Mass spectrometry facilities at
Boston College are supported by a grant from the NSF (CHE-
0619576).
future studies. With the present class of catalysts, reactions with
longer chain dialkylzinc reagents (e.g., n-Bu2Zn or (i-Pr)2Zn)
or Ph2Zn lead to low conversion and/or formation of racemic
secondary alcohols.
Investigations to identify catalytic systems that effectively
address the above problems and development of catalytic
enantioselective additions to other classes of ketones, as well
as applications to the synthesis of biologically active molecules,
constitute the focus of ongoing studies in these laboratories.
Supporting Information Available: Experimental procedures
and spectral data for substrates and products (PDF, CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. Financial support was generously provided
by the NIH (Grant GM-57212). We thank Mr. Adil Zhugralin
(Boston College) for his invaluable assistance in modeling studies,
related calculations, and numerous discussions; we also thank Ms.
Yunmi Lee (Boston College) for helpful discussions. We are
JA802935W
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J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9951